Inflammation plays a key role in many pathophysiological processes ranging from acute inflammation associated with ischemic/reperfusion or sterile injury, to chronic inflammation in response to bacterial infection, tumor growth, cardiovascular disease, or arthritis (Carden & Granger (2000) J. Pathol. 190: 255-266; Kvietys & Granger (2012) Free Radic. Biol. Med. 52: 556-592; Libby et al., (2009) J. Am. Coll. Cardiol. 54: 2129-2138; Medzhitov, R. (2008) Nature 454: 428-435; Querfurth & LaFerla (2010) N. Engl. J. Med. 362: 329-344; Zeyda & Stulnig (2009) Gerontology 55: 379-386). The ability to determine when and where inflammation is occurring is critical to both understanding the etiology of these diseases and optimizing therapeutic interventions against these potentially life-threatening acute and chronic conditions. Reactive oxygen and nitrogen species (RONS) are integral chemical mediators of both acute and chronic inflammation (Granger & Senchenkova (eds.) (2010) Inflammation and the Microcirculation. (Morgan and Claypool Life Sciences, San Rafael, Calif.)), and their generation occurs locally and early (within minutes) in the inflammatory process, preceding the arrival of inflammatory cells (e.g. non-resident macrophages, leukocytes) (Kvietys & Granger (2012) Free Radic. Biol. Med. 52: 556-592). Monitoring RONS levels thus provides an opportunity for molecular imaging of inflammation, the realization of which with high in vivo spatial and temporal resolution is however challenging and has yet to be achieved.
Most existing small-molecule and genetically encoded RONS imaging probes can only function in cell culture (Albers et al., (2006) J. Am. Chem. Soc. 128: 9640-9641; Belousov et al., (2006) Nat. Methods. 3: 281-286; Koide et al., (2007) J. Am. Chem. Soc. 129: 10324-10325; Lim et al., (2006) Nat. Chem. Biol. 2: 375-380; Mancini et al., (2008) J. Am. Chem. Soc. 130: 10836-10837; Miller et al., (2007) Nat. Chem. Biol. 3: 263-267). Of the few fluorescent probes tested in mouse models, none has been able to act systemically, but rather have been limited to local administration via intraperitoneal injection (Kundu et al., (2009) Angew Chem. Int. Ed. Engl. 48: 299-303; Lee et al., (2007) Nat. Mater. 6: 765-769; Oushiki et al., (2010) J. Am. Chem. Soc. 132: 2795-2801; Van de Bittner et al., (2010) Proc. Natl. Acad. Sci. U.S.A. 107: 21316-21321; Yuan et al., (2012) J. Am. Chem. Soc. 134: 1200-1211). While inflammation can often be localized to well-delineated regions of disease or injury, direct administration of probe is not always feasible and specific regions of inflammation are not necessarily known ab initio. Therefore, the inability of these probes to function after intravenous injection greatly constrains their utility to precisely identify inflammatory regions throughout the whole body and, as a result, fails to provide useful information for diagnosis of inflammation-related diseases and injury at the systemic level.